Strategies for treating degenerative retinal diseases are evolving at a rapid pace; however there exist major gaps impeding progress towards the ultimate audacious goal of regenerating neurons in the eye to restore sight. Technologies for monitoring the presence and health of individual photoreceptors and ganglion cells in living animal and human retinae are desperately needed. These tools would provide critical insight into the pathogenesis of a number of retinal and neuro-degenerative diseases; such insight is a requisite first step to developing the appropriate therapeutic approaches for a given patient/disease. Furthermore, improved visualization of cellular structure and function in patients with retinal degenerative diseases will permit scientists and clinicians to more precisely target and monitor the outcome of their therapeutic interventions. We have assembled a multidisciplinary research team uniquely equipped to address this major technological need. Drawing on our extensive experience in developing adaptive optics and retinal imaging tools, we propose to develop and disseminate four complementary platform/enabling technologies. We will leverage our existing collaborative relationships among all five participating sites, synergisic expertise, and access to extensive animal models along with an unrivaled patient population for testing these technologies. The specific technologies we propose to develop are: 1) Real-time retinal motion compensation, allowing retinal cellular-resolution imaging even in cases of extreme involuntary eye motion, like nystagmus; 2) Adaptive longitudinal chromatic aberration correction, allowing multi-wavelength, cellular-resolution retinal imaging; 3) Super- resolution line scanning ophthalmoscopy, to non-invasively image previously inaccessible cells and provide the largest image resolution improvement (> 50%) since the original demonstration of ophthalmic adaptive optics; and 4) High-throughput, opto-physiological method for assessing photoreceptor function with cellular resolution, providing a sensitive biomarker for assessing the function of regenerated/restored cells. A major strength of this application is that through our collaborative network we will validate the utility of these new technologies using regenerative therapies in both pre-clinical and clinical settings. This work will have a significant positive impact by enabling diagnosis of retinal disease and monitoring of retinal structure and function with unprecedented sensitivity and resolution. Finally, the focus of the proposed technologies will be photoreceptor and retinal ganglion cell imaging to explicitly advance the audacious goal, but they will not be limited to assessing any one therapeutic approach or cell type. Rather they will be generalizable and broadly applicable to all retinal cell types, retinal diseases, and therapeutic strategies.